Muscarinic receptors have at least five subtypes (M1 receptor, M2 receptor, M3 receptor, M4 receptor and M5 receptor) which are present in tissues or internal organs at different distribution levels. Non-selective muscarinic receptor antagonists represented by atropine and scopolamine, exhibit blocking actions of approximately the same level to these subtypes. These antagonists are effective for treating or preventing dyskinesia such as Parkinson's disease, drug-induced parkinsonism, dystonia and akinesia; diseases of digestive system such as pancreatitis, bilestone/cholecystitis, biliary dyskinesia and achalasia; pain, itch, cholinergic urticaria, irritable bowel syndrome, vomiting, nausea, dizziness, Meniere's disease, motion sickness such as space sickness, sea sickness and car sickness and urinary disturbance, but on the other hand induce such side effects as tachycardia, ocular hypertension, dry mouth, suppression of perspiration, mydriasis and constipation, which frequently prevent their use in the doses sufficient to exhibit their efficacies [cf. Basic and Clinical Pharmacology, 4th ed., (Appleton & Lange), pp. 83–92 (1989); Drug News & Perspective, Vol. 5, No. 6, pp. 345–352 (1992); The Merck Manual, 16th ed., pp. 1282–1283, P.1499 (1992)].
Recent research works indicate these side effects link to either one or both of M2 receptor and M3 receptor. That is, the side effect like tachycardia is considered to be mainly attributable to M2 receptor blockade, while dry mouth, suppression of perspiration, mydriasis and constipation are considered to be caused mainly by M3 receptor blockade [cf. Journal of Pharmacology & Experimental Therapeutics, Vol. 292, No. 3, pp. 877–885 (2000); Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 17, pp. 9579–9584 (2000)].
On the other hand, concerning dyskinesia such as Parkinson's disease, drug-induced parkinsonism, dystonia or akinesia, the involvemet of M4 receptors is suggested. [cf. Proceedings of the National Academy of Sciences of the United States of America, Vol. 96, No. 18, pp. 10483–10488 (1999)].
M4 receptor is also suggested to take part in various physiological actions such as gallbladder contraction, relaxation of bladder smooth muscles and pain [cf. Pharmacological Research, Vol. 39, No. 5, pp. 389–395 (1999); Journal of Pharmacology & Experimental Therapeutics, Vol. 283, No. 2, pp. 750–756 (1997); Journal of Autonomic Pharmacology, Vol. 18, No. 4, pp. 195–204 (1998); Journal of Pharmacology & Experimental Therapeutics, Vol. 282, No. 1, pp. 430–439 (1997)].
Furthermore, participation of M1 receptor or M4 receptor in vomiting, nausea, dizziness, Meniere's disease and motion sickness is suggested by the data shown in the following papers [cf. Neurochemistry International, Vol. 25, No. 5, pp. 455–464 (1994); Neuropharmacology, Vol. 27, No. 9, pp. 949–956 (1988)].
Considering the foregoing, substances which exhibit selective antagonistic activities at M1 or M4 receptors and weak blocking effect on M2 and M3 receptors can be expected to have therapeutic effects on such diseases as Parkinson's disease, drug-induced parkinsonism, dystonia, akinesia, pancreatitis, bilestone/cholecystitis, biliary dyskinesia, achalasia, pain, itch, cholinergic urticaria, irritable bowel syndrome, vomiting, nausea, dizziness, Meniere's disease, motion sickness such as space sickness, sea sickness and car sickness and urinary disturbance, without inducing such side effects as tachycardia, dry mouth, suppression of perspiration, mydriasis or constipation.
Compounds resembling compounds of the present invention in structure are disclosed, e.g., in International Publications WO 96/13262, WO 97/16192, WO 97/40035 and WO 99/32481, all of which share 1-(piperidin-4-yl)-1,3-dihydro-2H-benzimidazol-2-one skeleton, with the compounds of the present invention. Nevertheless those compounds which are disclosed in WO 97/16192, WO 97/40035 or WO 99/32481 have different kinds of functional groups substituting at 1-position of the piperidine ring in said skeletal structure, from those in the present invention. On the other hand, WO 96/13262 claims compounds with a broad scope of substituents at 1-position of the piperidine ring, which encompass a part of the compounds of the present invention, but the publication contains no specific disclosure about the compounds with a spacer between the piperidine ring and the nitrogen-containing alicyclic heterocyclic group, which is characteristic of the present invention.
Moreover, WO 99/32481 or WO 97/40035 contain no disclosure that their compounds particularly inhibit M1 or M4 receptors with high selectivity. While those compounds described in WO 97/16192 and WO 96/13262 are said to exhibit inhibitory activity against muscarinic M1, M2 and M4 receptors but only weak inhibitory action against M3 receptor, specific compounds or their inhibitory activity are not disclosed at all. Nor there is any disclosure about the compounds' having selective inhibitory action against M1 and M4 receptors.